Immediate "Kangaroo Mother Care" and Survival of Infants with Low Birth Weight.

BACKGROUND: "Kangaroo mother care," a type of newborn care involving skin-to-skin contact with the mother or other caregiver, reduces mortality in infants with low birth weight (<2.0 kg) when initiated after stabilization, but the majority of deaths occur before stabilization. The safety and efficacy of kangaroo mother care initiated soon after birth among infants with low birth weight are uncertain. METHODS: We conducted a randomized, controlled trial in five hospitals in Ghana, India, Malawi, Nigeria, and Tanzania involving infants with a birth weight between 1.0 and 1.799 kg who were assigned to receive immediate kangaroo mother care (intervention) or conventional care in an incubator or a radiant warmer until their condition stabilized and kangaroo mother care thereafter (control). The primary outcomes were death in the neonatal period (the first 28 days of life) and in the first 72 hours of life. RESULTS: A total of 3211 infants and their mothers were randomly assigned to the intervention group (1609 infants with their mothers) or the control group (1602 infants with their mothers). The median daily duration of skin-to-skin contact in the neonatal intensive care unit was 16.9 hours (interquartile range, 13.0 to 19.7) in the intervention group and 1.5 hours (interquartile range, 0.3 to 3.3) in the control group. Neonatal death occurred in the first 28 days in 191 infants in the intervention group (12.0%) and in 249 infants in the control group (15.7%) (relative risk of death, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P = 0.001); neonatal death in the first 72 hours of life occurred in 74 infants in the intervention group (4.6%) and in 92 infants in the control group (5.8%) (relative risk of death, 0.77; 95% CI, 0.58 to 1.04; P = 0.09). The trial was stopped early on the recommendation of the data and safety monitoring board owing to the finding of reduced mortality among infants receiving immediate kangaroo mother care. CONCLUSIONS: Among infants with a birth weight between 1.0 and 1.799 kg, those who received immediate kangaroo mother care had lower mortality at 28 days than those who received conventional care with kangaroo mother care initiated after stabilization; the between-group difference favoring immediate kangaroo mother care at 72 hours was not significant. (Funded by the Bill and Melinda Gates Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12618001880235; Clinical Trials Registry-India number, CTRI/2018/08/015369.).

Antenatal Dexamethasone for Early Preterm Birth in Low-Resource Countries.

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P = 0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P = 0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection. (Funded by the Bill and Melinda Gates Foundation and the World Health Organization; Australian and New Zealand Clinical Trials Registry number, ACTRN12617000476336; Clinical Trials Registry-India number, CTRI/2017/04/008326.).

Target product profile: aerosolized surfactant for neonatal respiratory distress.

Treatment with surfactant has been found to improve the survival rate of neonates with respiratory distress syndrome, particularly preterm infants. However, surfactant is usually administered by endotracheal intubation and generally only in level-3 neonatal intensive care units. Recent improvements in aerosolization technology have raised the possibility that aerosolized surfactant could now be given in wider range of settings, including resource-poor settings. Consequently, the World Health Organization has developed a target product profile for product developers that describes the optimal and minimal characteristics of an aerosolized surfactant for treating neonates with respiratory distress syndrome in low- and middle-income countries. Development of the target product profile involved a scoping review of systematic reviews and target product profiles of aerosolized surfactant, the constitution of an international expert advisory group, consultations with medical professionals from a wide range of countries and a public consultation. The resulting target product profile specifies that the surfactant and its associated aerosolization device should ideally, among other characteristics: (i) be at least as safe and effective as current intratracheal surfactant; (ii) produce a rapid clinical improvement; (iii) be easy to transport and use (e.g. by nurses in level-2 health-care facilities in low- and middle-income countries); (iv) be affordable for low- and middle-income countries; and (v) be stable when stored in hot and humid conditions. In addition, the aerosolization device should be capable of daily use for many years. The introduction of an effective aerosolized surfactant globally could substantially reduce neonatal mortality due to respiratory distress syndrome.

Le traitement par surfactant permet d'améliorer le taux de survie des nouveau-nés souffrant d'un syndrome de détresse respiratoire, en particulier les nourrissons prématurés. Pourtant, ce surfactant est généralement administré par intubation endotrachéale et, la plupart du temps, uniquement dans les unités de soins intensifs néonatals de niveau 3. Les récents progrès réalisés dans le domaine des technologies d'aérosolisation laissent entrevoir la possibilité d'administrer dorénavant un surfactant en aérosol dans d'autres cadres, y compris dans des lieux où les ressources sont limitées. L'Organisation mondiale de la Santé a donc développé un profil de produit cible à l'attention des laboratoires, qui détaille les caractéristiques minimales et optimales d'un surfactant en aérosol destiné à la prise en charge des nouveau-nés souffrant d'un syndrome de détresse respiratoire dans les pays à revenu faible et intermédiaire. Ce document est le fruit d'une analyse exploratoire de revues systématiques et de profils de surfactants en aérosol; un groupe consultatif d'experts internationaux a été constitué, des professionnels de la santé originaires de nombreux pays ont été sollicités, et une consultation publique a été organisée. Le profil de produit cible qui en résulte précise que le surfactant et son dispositif d'aérosolisation doivent idéalement présenter une série de caractéristiques, notamment: (i) être au moins aussi sûrs et efficaces que le surfactant intratrachéal actuel; (ii) entraîner une amélioration clinique rapide; (iii) être faciles à transporter et à utiliser (par exemple par le personnel infirmier de niveau 2, au sein d'établissements de santé dans des pays à revenu faible et intermédiaire); (iv) être abordables pour les pays à revenu faible et intermédiaire; et enfin, (v) demeurer stables quand ils sont stockés dans un environnement chaud et humide. En outre, le dispositif d'aérosolisation doit pouvoir être employé au quotidien pendant plusieurs années. Le lancement d'un surfactant en aérosol à l'échelle mondiale pourrait réduire considérablement la mortalité néonatale due au syndrome de détresse respiratoire.

Se ha observado que el tratamiento con sustancias tensioactivas mejora la tasa de supervivencia de los neonatos con síndrome de dificultad respiratoria, especialmente los prematuros. Sin embargo, la sustancia tensioactiva suele administrarse mediante intubación endotraqueal y, por lo general, solo en unidades de cuidados intensivos neonatales de nivel 3. Las mejoras recientes en la tecnología de aerosolización han planteado la posibilidad de que la sustancia tensioactiva en aerosol se pueda administrar ahora en más entornos, incluidos los de escasos recursos. En consecuencia, la Organización Mundial de la Salud ha desarrollado un perfil de producto específico para los desarrolladores de productos que describe las características óptimas y mínimas de una sustancia tensioactiva en aerosol para el tratamiento de neonatos con síndrome de dificultad respiratoria en países de ingresos bajos y medios. El desarrollo del perfil de producto específico implicó una revisión del alcance de las revisiones sistemáticas y los perfiles de producto específicos de la sustancia tensioactiva en aerosol, la constitución de un grupo asesor internacional de expertos, consultas con profesionales médicos de diversos países y una consulta pública. El perfil de producto específico obtenido indica que lo ideal sería que la sustancia tensioactiva y su dispositivo de aerosolización asociado tuvieran, entre otras, las siguientes características: (i) ser al menos tan seguros y eficaces como la sustancia tensioactiva intratraqueal actual; (ii) producir una mejora clínica rápida; (iii) ser fáciles de transportar y utilizar (p. ej. por el personal de enfermería de los centros sanitarios de nivel 2 de los países de ingresos bajos y medios); (iv) ser asequibles para los países de ingresos bajos y medios; y (v) ser estables cuando se almacenan en condiciones de calor y humedad. Además, el dispositivo de aerosolización se debería poder utilizar a diario durante muchos años. La introducción de una sustancia tensioactiva en aerosol eficaz a nivel mundial podría reducir de manera sustancial la mortalidad neonatal causada por el síndrome de dificultad respiratoria.

The beneficial effect of early and prolonged kangaroo mother care on long-term neuro-developmental outcomes in low birth neonates - A cohort study.

AIM: Kangaroo mother care (KMC) has immense short-term benefits, but data on long-term outcomes are scarce. Hence, this study aimed to compare the neurodevelopmental outcomes at 12 months of corrected age (CA) in infants <2000 g receiving early and prolonged KMC to a control group. METHODS: This was a cohort study that was conducted from January 2017 to November 2018. All neonates<2000 g were eligible for the study. Neonates that received early initiation (<72 h of life) and prolonged KMC comprised the intervention group and were compared to neonates without the intervention. Bayley Scales of Infant and Toddler Development, Third edition (BSID-III) was done at 12 months of CA, and this was analysed using t-test and multi-linear regression analysis. RESULTS: There were 75 neonates in the intervention and 69 in the control group. Baseline characteristics were comparable. We found higher composite scores for cognition (110.38 ± 9.89 vs. 105.44 ± 8.77, p value = 0.023), language (107.51 ± 10.72 vs. 101.05 ± 12.06, p value = 0.014) and adaptive behaviour (87.97 ± 9.97 vs. 80 ± 9.1, p value<0.001) in the early and prolonged KMC group in comparison to the control group. CONCLUSION: Infants with early and prolonged KMC have better neurodevelopmental outcomes in terms of cognition, language and adaptive behaviour at 12 months of CA.

Accelerated scale-up of Kangaroo Mother Care: Evidence and experience from an implementation-research initiative in south India.

AIM: Though Kangaroo Mother Care (KMC) has demonstrated benefits for low birth weight newborns, coverage continues to be low in India. As part of a World Health Organization (WHO) multi-country study, we explored intervention models to accelerate KMC coverage in a high priority district of Karnataka, India. METHODS: We used implementation-research methods, formative assessments and quality improvement approaches to design and scale-up interventions. Evaluation was done using prospective cohort study design; data were collected from facility records, and client interviews during KMC initiation, at discharge and at home after discharge. RESULTS: KMC was initiated at health facilities for 87.6% of LBW babies under 2000 g. At discharge, 85.0% received KMC; 67.9% continued to receive KMC at home on the 7th day post-discharge. The interventions included training, mentoring and constant advocacy at many levels: public health facilities, private sector and the community. Innovations like a KMC case sheet, counselling, peer support group triggered KMC in the facilities; a KMC-link card, a microplanning and communication tool for CHWs helped to sustain practice at homes. CONCLUSION: The study provides a novel approach to designing and scaling up interventions and suggests lessons that are applicable to KMC as well as to broader reproductive, maternal, neonatal and child health programmes.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane.

PURPOSE: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). METHODS: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). RESULTS: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. CONCLUSION: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

The effect of exchange transfusion on mortality in neonatal sepsis: a meta-analysis.

Although antimicrobials are the cornerstone of neonatal sepsis management, adjunctive therapies are required to improve outcomes. The aim of our study was to evaluate the effect of exchange transfusion (ET) on mortality (primary outcome) in neonatal sepsis, as well as on immunoglobulin, complement and neutrophil levels and assess its complications (secondary outcomes). Databases searched include PubMed, NCBI, Google Scholar, CINHAL, Ovid and Scopus. Randomized controlled trials (RCTs), controlled observational studies (COSs) and uncontrolled observational studies (UOSs) reporting mortality data from using ET in neonatal sepsis were included. Studies with additional interventions, non-septic ET indications and populations aged > 28 days were excluded. Data extracted include demographics, features of study, sepsis and ET, as well as mortality rates, immunological and laboratory changes and complications. Data was meta-analysed and displayed using forest plots. The meta-analysis of 14 studies (3 RCTs, 11 COSs) revealed a mortality benefit in septic neonates who underwent ET-RR 0.72 (CI 0.61-0.86, p = 0.01) and a significant increase in pooled immunological parameters (immunoglobulin, complement levels) (SMD 1.13, [0.25, 2.02], p = 0.02) and neutrophil levels (SMD 1.07 [0.04, 2.11], p = 0.03) compared to controls. The descriptive analysis of 9 UOSs revealed thrombocytopenia as the most frequently reported complication (n = 48). Moderate-high risk of bias was largely due to inadequate sample sizes and follow-up durations.Conclusion: Currently, the use of ET in neonatal sepsis is not directly recommended due to low certainty of evidence, inadequate power and moderate-high risk of bias and heterogeneity.Trial registration: PROSPERO (CRD42020176629) ( https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=176629 ) What is Known: • Exchange transfusion is one of the adjunctive methods for treatment of neonatal sepsis. What is New: • The pooled analysis of all studies shows that exchange transfusion has a low certainty of evidence in the context of neonatal mortality. However, at this point, this intervention cannot be refuted or recommended due to heterogeneity of studies and inadequate power.

Antenatal corticosteroids for early preterm birth: implementation strategy lessons from the WHO ACTION-I trial.

The WHO ACTION-I trial, the largest placebo-controlled trial on antenatal corticosteroids (ACS) efficacy and safety to date, reaffirmed the benefits of ACS on mortality reduction among early preterm newborns in low-income settings. We discuss here lessons learned from ACTION-I trial that are relevant to a strategy for ACS implementation to optimize impact. Key elements included (i) gestational age dating by ultrasound (ii) application of appropriate selection criteria by trained obstetric physicians to identify women with a likelihood of preterm birth for ACS administration; and (iii) provision of a minimum package of care for preterm newborns in facilities. This strategy accurately identified a large proportion of women who eventually gave birth preterm, and resulted in a 16% reduction in neonatal mortality from ACS use. Policy-makers, programme managers and clinicians are encouraged to consider this implementation strategy to effectively scale and harness the benefits of ACS in saving preterm newborn lives.

Safety and Efficacy of First-Line Pembrolizumab in Black Patients with Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION: Pembrolizumab, an immune checkpoint inhibitor (ICI), has become an integral part of front-line treatment of metastatic non-small cell lung cancer (NSCLC). However, pivotal trials had significant underrepresentation of Black patients (pts). Lack of sufficient evidence regarding safety and efficacy of ICIs among minority racial groups poses a challenge in delivery of optimal cancer directed care. METHODS: We retrospectively reviewed pts with stage IV NSCLC treated with first-line pembrolizumab across three MedStar facilities between January 1, 2014, and May 3, 2019. Progression-free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using the Kaplan-Meier method. Immune-related adverse events (irAEs) were assessed according to Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0). RESULTS: In total, 136 pts were identified, with 74 (54.4%) White, 53 (39%) Black, 2 (1.5%) Asian, and 7 (5.1%) other racial groups. Median age was 70 years in White pts and 65 years in Black pts (p < .01). There was no difference in median PFS (5.7 vs. 5.9 months; p = .651) or OS (11.8 vs. 12.4 months; p = .949) between White and Black pts. In the subset of patients whose tumors had high programmed death-ligand 1 (PD-L1) expression (≥50%), there was still no difference in efficacy by race. Median PFS (8.7 vs. 3.9 months; p = .843) and OS (14.7 vs. 11.3 months; p = .581) in White versus Black pts were not different. Incidence of irAEs in White versus Black pts was 24.3% and 22.6%, respectively (p = .83). CONCLUSION: We found no major differences in either safety or efficacy of first-line pembrolizumab between White and Black pts. Use of first-line pembrolizumab-based treatment in Black pts with stage IV NSCLC is safe and efficacious, based on these real-world data. IMPLICATIONS FOR PRACTICE: Immunotherapy has revolutionized treatment of solid and hematological malignancies. There are certain populations of patients underrepresented in the original trials including minority racial groups, patients with autoimmune diseases, and those with chronic viral illnesses. Our study focuses on Black patients with metastatic lung cancer who received pembrolizumab and concludes similar safety and response to treatment when compared with White patients. Black patients are an important demographic group in clinical practice often facing systemic health care disparities. This study paves a path for future studies in underrepresented populations receiving immunotherapy across various malignancies.

Quality improvement initiative to improve the duration of kangaroo mother care for twin preterm neonates born at a tertiary care hospital in resource-limited settings.

AIM: Kangaroo mother care (KMC) can be challenging in multiple births and more so in resource-limited settings. This study aims at increasing the mean duration of KMC with early initiation in twin preterm neonates born at a tertiary care hospital using a quality improvement (QI) initiative. METHODS: Barriers for poor KMC practice in twin preterm neonates born at the tertiary care hospital were analysed and baseline data were collected over a period of 4 months using a predesigned proforma. A QI team was formed and suggested solutions were prioritised through focus group discussions in the form of Plan-Do-Study-Act (P-D-S-A) cycles. Each cycle was of one-month duration and three cycles were implemented, followed by the sustenance phase studied at 1-month post-implementation. RESULTS: There were a total of 238 twin deliveries in the study period, of which 169 twin pairs were included in the study. At the end of implementation, the average day of initiation of KMC improved from 8th to 3rd day of life and the duration of KMC increased significantly from an average of 2.70 h/infant/day to 7.88 h/infant/day. CONCLUSION: This QI project focused on the improvement of KMC practice in twin preterm neonates in a tertiary care hospital where results were achieved with maximal utilisation of available hospital resources and low-cost interventions. This study design is generalizable to other hospitals in resource-limited settings where family participatory care can be strengthened to overcome the challenges of KMC in multiple births.

Quantitative Analysis of the Potency of Equimolar Two-Drug Combinations and Combi-Molecules Involving Kinase Inhibitors In Vitro: The Concept of Balanced Targeting.

The median-effect principle proposed by Chou and Talalay is the most effective approach to parameterize interactions between several agents in combination. However, this method cannot be used to evaluate the effectiveness of equimolar drug combinations, which are comparative references for dual-targeting molecular design. Here, using data acquired through the development of "combi-molecules" blocking two kinases (e.g., EGFR-c-Src and EGFR-c-Met), we established potency indices for equimolar and dual-targeted inhibitors. If the fold difference (κ) between the IC50 of the two individual kinase inhibitors was >6, the IC50 of their equimolar combination resembled that of the more potent inhibitor. Hence, the "combi-targeting" of the two kinases was considered "imbalanced" and the combination ineffective. However, if κ ≤ 6, the IC50 of the combination fell below that of each individual drug and the combi-targeting was considered "balanced" and the combination effective. We also showed that combi-molecules should be compared with equimolar combinations only under balanced conditions and propose a new parameter Ω for validating their effectiveness. A multi-targeted drug is effective if Ω < 1, where Ω is defined as the IC50 of the drug divided by that of the corresponding equimolar combination. Our study provides a methodology to determine the in vitro potency of equimolar two-drug combinations as well as combi-/hybrid molecules inhibiting two different kinase targets.

A multitargeted probe-based strategy to identify signaling vulnerabilities in cancers.

Most cancer cells are dependent on a network of deregulated signaling pathways for survival and are insensitive, or rapidly evolve resistance, to selective inhibitors aimed at a single target. For these reasons, drugs that target more than one protein (polypharmacology) can be clinically advantageous. The discovery of useful polypharmacology remains serendipitous and is challenging to characterize and validate. In this study, we developed a non-genetic strategy for the identification of pathways that drive cancer cell proliferation and represent exploitable signaling vulnerabilities. Our approach is based on using a multitargeted kinase inhibitor, SM1-71, as a tool compound to identify combinations of targets whose simultaneous inhibition elicits a potent cytotoxic effect. As a proof of concept, we applied this approach to a KRAS-dependent non-small cell lung cancer (NSCLC) cell line, H23-KRASG12C Using a combination of phenotypic screens, signaling analyses, and kinase inhibitors, we found that dual inhibition of MEK1/2 and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) is critical for blocking proliferation in cells. Our work supports the value of multitargeted tool compounds with well-validated polypharmacology and target space as tools to discover kinase dependences in cancer. We propose that the strategy described here is complementary to existing genetics-based approaches, generalizable to other systems, and enabling for future mechanistic and translational studies of polypharmacology in the context of signaling vulnerabilities in cancers.

The Thin But Fat Phenotype is Uncommon at Birth in Indian Babies.

BACKGROUND: Indian babies are hypothesized to be born thin but fat. This has not been confirmed with precise measurements at birth. If it is true, it could track into later life and confer risk of noncommunicable diseases (NCDs). OBJECTIVES: Primarily, to accurately measure percentage of body fat (%BF) and body cell mass (BCM) in Indian babies with normal birth weight, compare them across different gestational ages and sex, and test the hypothesis of the thin but fat phenotype in Indian babies. Secondarily, to examine the relation between body weight and body fat in Indian babies. METHODS: Term newborns (n = 156) weighing ≥2500 g, from middle socioeconomic status mothers were recruited in Bengaluru, India, and their anthropometry, %BF (air displacement plethysmography), and BCM (whole-body potassium counter) were measured. Maternal demography and anthropometry were recorded. The mean %BF and its dispersion were compared with earlier studies. The relation between newborn %BF and body weight was explored by regression analysis. RESULTS: Mean birth weight was 3.0 ± 0.3 kg, with mean %BF 9.8 ± 3.5%, which was comparable to pooled estimates of %BF from published studies (9.8%; 95% CI: 9.7, 10.0; P > 0.05). Appropriate-for-gestational age (AGA) babies had higher %BF (1.8%) compared to small-for-gestational age (SGA) babies (P < 0.01). Mean %BCM of all babies at birth was 35.4 ± 10.5%; AGA babies had higher %BCM compared to SGA babies (7.0%, P < 0.05). Girls in comparison to boys had significantly higher %BF and lower %BCM. Body weight was positively associated with %BF. CONCLUSION: Indian babies with normal birth weight did not demonstrate the thin but fat phenotype. Body weight and fat had positive correlation, such that SGA babies did not show a preservation of their %BF. These findings will have relevance in planning optimal interventions during early childhood to prevent NCDs risk in adult life.

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). METHODS: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. RESULTS: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%). CONCLUSIONS: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

Kangaroo Mother Care in Hospitalized Low Birth-Weight Infants on Respiratory Support: A Feasibility and Safety Study.

BACKGROUND: Low birth-weight (LBW) infants on respiratory support are often deprived of kangaroo mother care (KMC) due to fear of instability. Data on safety of KMC in these infants are lacking. PRIMARY OBJECTIVE: To determine the feasibility of KMC in LBW infants on continuous positive airway pressure or synchronized intermittent mandatory ventilation. SECONDARY OBJECTIVES: To compare vital signs (heart rate [HR], respiration, temperature, and SpO2) and ventilatory parameters (FIO2, peak inspiratory pressure [PIP], and positive end-expiratory pressure [PEEP]) before, during, and after KMC, and assess the mother's perception of the KMC intervention. METHODS: LBW infants stable on respiratory support were given KMC for 1 hour. Vital signs and ventilator parameters were recorded before, every 15 minutes during and after KMC. Feasibility was defined as continuation of KMC for 1 hour without interruption, with stable vital signs (HR > 100/min, SpO2 > 90%, and temperature 36.5°C-37.5°C) and ventilator parameters (no change in PIP, PEEP, or increase in FIO2 not more than 0.1) without tube dislodgement. RESULTS: Twenty LBW infants with a mean birth weight of 1390 ± 484 g were included. All infants completed 1-hour duration of KMC without interruption. No significant changes in temperature, respiratory rates, or saturations were noted. The HR and FIO2 were marginally higher during KMC than before or after (HR before 147.3 ± 11.5, during 150.8 ± 11, and after 147.3 ± 11.1, P = .04; FIO2 before 30.6 ± 8.1, during 31.8 ± 8.1, and after 30.7 ± 8.0, P = .034). No accidental extubation or dislodgement of lines occurred. Most mothers were happy. IMPLICATIONS FOR PRACTICE: The vital signs were stable during KMC. KMC is feasible in infants receiving respiratory support. IMPLICATIONS FOR RESEARCH: Effectiveness of early initiation and prolonged duration of KMC.

Correlation between Perfusion Index and CRIB Score in Sick Neonates Admitted to a Tertiary Center.

Objective: The study was to determine the correlation of Perfusion Index (PI) and Clinical Risk Index for Babies (CRIB) score, in assessing the severity of illness in sick neonates. Methods: This was a cross-sectional study conducted at a tertiary care Neonatal Intensive Care Unit (NICU). All eligible neonates, both term and preterm, admitted to the high-dependency unit of the NICU were included, after parental consent. Relevant details of history and examination were collected with a structured proforma. Severity of illness was assessed using CRIB score within 12 h of admission. PI was recorded within 24 h of admission, and babies were examined for the presence or absence of shock and their outcome was documented. The correlation coefficient between PI and CRIB score was derived. Results: A total of 200 eligible newborns were enrolled. The mean gestational age of the neonates was 34 weeks. The median [interquartile range (IQR)] CRIB score was 1.00 (0.00, 3.00), and PI was 1.400 (0.93, 2.30). The Spearman's rank correlation coefficient between PI and CRIB score was -0.41 with p value <0.05. The median PI of neonates with CRIB score ≤5, 6-10 and >10 was 1.50, 0.74, 0.67, respectively (p value <0.0001). The median (IQR) PI of babies with shock and without shock was 0.63 (0.43, 0.84) and 1.58 (1.19, 2.41), respectively, with p value <0.001. Conclusion: PI has a negative correlation with CRIB score and can be used to assess the severity of illness in sick neonates.

Breast Milk Quality Improvement Bundle for Very Low Birth Weight Neonates.

PURPOSE: To assess the effect of a quality improvement (QI) bundle on improving breast milk output among very low birth weight (VLBW) mothers. DESIGN: Before and after nonrandomized QI project. SAMPLE: Mothers who delivered a VLBW infant in October and November 2015 were the prospective cohort. Those who delivered a VLBW infant in August and September 2015 were the retrospective cohort. The QI bundle consisted of early expression of milk, use of breast pumps, frequent expressions, videos, and regular counseling. This bundle was done for the prospective cohort. OUTCOMES MEASURES: Quantity of expressed breast milk on day 7. RESULTS: There were 13 mothers in the retrospective cohort and 18 mothers in the prospective one. The mean birth weight (1297.80 and 1207.70 g, p = .19) and gestation (32.5 and 31.5 wk, p = .27) were similar. There was a significant increase in the milk output on day 7 in the prospective group 113.6 ± 45 vs 182 ± 63 mL (p = .001).

Effect of Epidural Infusion Bolus Delivery Rate on the Duration of Labor Analgesia: A Randomized Clinical Trial.

BACKGROUND: Programmed intermittent boluses of local anesthetic have been shown to be superior to continuous infusions for maintenance of labor analgesia. High-rate epidural boluses increase delivery pressure at the catheter orifice and may improve drug distribution in the epidural space. We hypothesized that high-rate drug delivery would improve labor analgesia and reduce the requirement for provider-administered supplemental boluses for breakthrough pain. METHODS: Nulliparous women with a singleton pregnancy at a cervical dilation of less than or equal to 5 cm at request for neuraxial analgesia were eligible for this superiority-design, double-blind, randomized controlled trial. Neuraxial analgesia was initiated with intrathecal fentanyl 25 µg. The maintenance epidural solution was bupivacaine 0.625 mg/ml with fentanyl 1.95 µg/ml. Programmed (every 60 min) intermittent boluses (10 ml) and patient controlled bolus (5 ml bolus, lockout interval: 10 min) were administered at a rate of 100 ml/h (low-rate) or 300 ml/h (high-rate). The primary outcome was percentage of patients requiring provider-administered supplemental bolus analgesia. RESULTS: One hundred eight women were randomized to the low- and 102 to the high-rate group. Provider-administered supplemental bolus doses were requested by 44 of 108 (40.7%) in the low- and 37 of 102 (36.3%) in the high-rate group (difference -4.4%; 95% CI of the difference, -18.5 to 9.1%; P = 0.67). Patient requested/delivered epidural bolus ratio and the hourly bupivacaine consumption were not different between groups. No subject had an adverse event. CONCLUSIONS: Labor analgesia quality, assessed by need for provider- and patient-administered supplemental analgesia and hourly bupivacaine consumption was not improved by high-rate epidural bolus administration.

Gastric Residual Volumes Versus Abdominal Girth Measurement in Assessment of Feed Tolerance in Preterm Neonates: A Randomized Controlled Trial.

BACKGROUND: Preterm neonates often have feed intolerance that needs to be differentiated from necrotizing enterocolitis. Gastric residual volumes (GRV) are used to assess feed tolerance but with little scientific basis. PURPOSE: To compare prefeed aspiration for GRV and prefeed measurement of abdominal girth (AG) in the time taken to reach full feeds in preterm infants. METHODS: This was a randomized controlled trial. Infants with a gestational age of 27 to 37 weeks and birth weight of 750 to 2000 g, who required gavage feeds for at least 48 hours, were included. Infants were randomized into 2 groups: infants in the AG group had only prefeed AG measured. Those in the GRV group had prefeed gastric aspiration obtained for the assessment of GRV. The primary outcome was time to reach full enteral feeds at 150 mL/kg/d, tolerated for at least 24 hours. Secondary outcomes were duration of hospital stay, need for parenteral nutrition, episodes of feed intolerance, number of feeds withheld, and sepsis. RESULTS: Infants in the AG group reached full feeds earlier than infants in the GRV group (6 vs 9.5 days; P = .04). No significant differences were found between the 2 groups with regard to secondary outcomes. IMPLICATIONS FOR PRACTICE: Our research suggests that measurement of AG without assessment of GRV enables preterm neonates to reach full feeds faster than checking for GRV. IMPLICATIONS FOR RESEARCH: Abdominal girth measurement as a marker for feed tolerance needs to be studied in infants less than 750 g and less than 26 weeks of gestation.

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial.

BACKGROUND: In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS: In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. FINDINGS: Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029). INTERPRETATION: Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. FUNDING: Merck & Co.